Simian immunodeficiency virus (SIV) and related primate lentiviruses have been used to evaluate the relative efficacy of vaccine approaches and to examine correlates of protection. It was previously reported that envelope (gp160)-based vaccines, used in a live recombinant virus priming and subunit protein boosting regimen, protected macaques from intravenous challenge by a cloned homologous virus SIVmneE11S. Immunity elicited by this approach was protective against intrarectal challenge by E11S grown on HuT-78 cells and against intravenous challenge by the same virus grown on primary macaque peripheral blood mononuclear cells. It has now been demonstrated that priming with live recombinant virus was more effective than immunization with subunit gp160 alone in eliciting protective immunity, indicating a potential role of endogenous presentation of antigens and cell-mediated immunity in protection. Priming with recombinant virus and boosting with surface antigen (gp130) generated a similar level of neutralizing antibodies as was induced by gp160 immunization. However, gp130 was not as effective as gp160 in inducing protective immunity, indicating a potential role for the transmembrane protein in presenting functionally important epitopes. The role of core antigens in inducing protective immunity was also examined. Immunization with gag-pol antigens alone failed to generate any neutralizing antibody and was not protective against a homologous SIV challenge. However, virus load in immunized animals was 100-fold lower than that of nonimmunized control animals, suggesting a role for core antigen-specific responses in controlling acute infection. Future studies will determine if the inclusion of these additional antigens will broaden the protective response to include protection from a challenge with heterologous viruses.